title: C-Glucosides with heteroaryl thiophene as novel sodium-dependent glucose cotransporter 2 inhibitors.
abstract: Canagliflozin (1), a novel inhibitor for sodium-dependent glucose cotransporter 2 (SGLT2), has been developed for the treatment of type 2 diabetes. To investigate the effect of replacement of the phenyl ring in 1 with heteroaromatics, C-glucosides 2 were designed, synthesized, and evaluated for their inhibitory activities against SGLT2. Of these, 3-pyridyl, 2-pyrimidyl or 5-membered heteroaryl substituted derivatives showed highly potent inhibitory activity against SGLT2, while 5-pyrimidyl substitution was associated with slightly reduced activity. In particular, 2g (TA-3404) had remarkable anti-hyperglycemic effects in high-fat diet fed KK (HF-KK) mice.
authors.affiliation: Medicinal Chemistry Research Laboratories, Mitsubishi Tanabe Pharma Corporation, 2-2-50 Kawagishi, Toda, Saitama 335-8505, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Koga
authors.forename: Shigeki
authors.initials: S
authors.lastname: Sakamaki
authors.forename: Mitsuya
authors.initials: M
authors.lastname: Hongu
authors.forename: Eiji
authors.initials: E
authors.lastname: Kawanishi
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Sakamoto
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Kimata
authors.forename: Keiko
authors.initials: K
authors.lastname: Nakayama
authors.forename: Chiaki
authors.initials: C
authors.lastname: Kuriyama
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Matsushita
authors.forename: Kiichiro
authors.initials: K
authors.lastname: Ueta
authors.forename: Minoru
authors.initials: M
authors.lastname: Tsuda-Tsukimoto
authors.forename: Sumihiro
authors.initials: S
authors.lastname: Nomura
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D016466:CHO Cells; D000068896:Canagliflozin; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D059305:Diet, High-Fat; D005960:Glucosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D009005:Monosaccharides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011485:Protein Binding; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D051269:Sodium-Glucose Transporter 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051297:Sodium-Glucose Transporter 2 / Q000235:genetics / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes / Q000737:chemistry*
chemical_list: D001786:Blood Glucose; D005960:Glucosides; D007004:Hypoglycemic Agents; D009005:Monosaccharides; D011725:Pyridines; D051269:Sodium-Glucose Transporter 1; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C586765:TA-3404; D013876:Thiophenes; D000068896:Canagliflozin
keywords: Canagliflozin; Glucoside; SGLT2 inhibitor; Thiophene; Type 2 diabetes